PROJECT SUMMARY Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly aggressive soft tissue sarcomas that arise from peripheral nerves or the cells associated with nerve sheaths. They develop with high frequency in patients with neurofibromatosis (NF1), and also sporadically in the general population or as a secondary malignancy following radiation treatment. These tumors have high rates of metastasis to distant organs, and do not respond adequately to standard chemotherapy or radiation. The only curative method involves wide surgical excision. However, MPNSTs typically reside in close proximity to critical structures or present with metastatic disease, and therefore are not often amenable to surgical cure. Improved therapies for MPNSTs are urgently needed to improve survival rates and quality of life. We previously reported that the intracellular chaperone cyclophilin B (CypB) plays a critical role in supporting the survival of many tumors, particularly those of the nervous system, including Glioblastoma multiforme (GBM). Knockdown or small molecule inhibition of CypB caused tumor cell death through a non-apoptotic mechanism characterized by massive cytosolic vacuolization. In new work, we have conducted a high throughput screen to search for novel CypB binding compounds with improved anti-cancer activity. One compound, ?MLS042?, was significantly more effective than previously characterized CypB inhibitors, and was used as a lead compound to generate a family of related molecules. The most active, ?SBI298?, forms the basis for this proposal. MLS042 and SBI298 have selective cytotoxic activity against a range of tumor cell types. Of the tumor types we have tested to date, MPNST cells have the highest sensitivity to cell killing by MLS042 and SBI298. Preliminary tests in mice reveal that these compounds are relatively well tolerated, thus leading to the central hypothesis of this application that SBI298 will prove to be safe and effective as a new therapeutic agent for treatment of MPNST in preclinical testing. The goal of this proposal is to conduct preclinical in vitro and in vivo testing of SBI298 and a focused set of related analogs to demonstrate that it has sufficient biological activity to warrant further development for treatment of MPNST. We anticipate that these studies will validate the significant roles of CypB and PIKfyve in tumor cell survival, and will lead to a new, highly effective therapeutic for MPNST and potentially for other malignancies, as well. !